Characteristics and mortality of 561,379 hospitalized COVID-19 patients in Germany until December 2021 based on real-life data

The ongoing SARS-CoV-2 pandemic is characterized by poor outcome and a high mortality especially in the older patient cohort. Up to this point there is a lack of data characterising COVID-19 patients in Germany admitted to intensive care (ICU) vs. non-ICU patients. German Reimbursement inpatient data covering the period in Germany from January 1st, 2020 to December 31th, 2021 were analyzed. 561,379 patients were hospitalized with COVID-19. 24.54% (n = 137,750) were admitted to ICU. Overall hospital mortality was 16.69% (n = 93,668) and 33.36% (n = 45,947) in the ICU group. 28.66% (n = 160,881) of all patients suffer from Cardiac arrhythmia and 17.98% (n = 100,926) developed renal failure. Obesity showed an odds-ratio ranging from 0.83 (0.79–0.87) for WHO grade I to 1.13 (1.08–1.19) for grade III. Mortality-rates peaked in April 2020 and January 2021 being 21.23% (n = 4539) and 22.99% (n = 15,724). A third peak was observed November and December 2021 (16.82%, n = 7173 and 16.54%, n = 9416). Hospitalized COVID-19 patient mortality in Germany is lower than previously shown in other studies. 24.54% of all patients had to be treated in the ICU with a mortality rate of 33.36%. Congestive heart failure was associated with a higher risk of death whereas low grade obesity might have a protective effect on patient survival. High admission numbers are accompanied by a higher mortality rate.

The ongoing COVID-19 pandemic is affecting people worldwide since the first reported case. Up to the end of October, more than 246 million cases and up to 5 million deaths have been reported 1,2 . The number of unreported cases is probably much higher. This makes the COVID-19 pandemic one of the deadliest in history.
Infection with the SARS-CoV-2 virus presents with a wide variety of symptoms-From none to life threatening. This complicates the detection and containment of the virus. With the worldwide spread of the SARS-CoV-2 virus, a burden has been placed on the health care systems worldwide. Especially the intensive care units (ICU) as a limited resource were occupied with the care of COVID-19 patients. In some countries, the ICU capacities reached their limits 3,4 , resulting in catastrophic outcomes for the patients. Over the pandemic, admission rates to ICU and mortality rate varied strongly. In the early phase of the pandemic, first reports and characterisations based on smaller populations mainly in China suggested only mild symptoms in 80% of the cases [5][6][7][8] . 20% needed hospital treatment and 20% of the hospitalized patients required ICU treatment 6,7,9 . Those numbers vary within the European Union 10 . Estimates suggest that between 10 and 20% of SARS-CoV-2 patients become so severely ill, that hospital treatment is required. In addition, the proportion of infected people who require intensive care also varies between 5 and 32% 10,11 . Therefore, it is important to be able to adequately calculate the resources of the health care system to avoid a collapse of the system in the event of another wave. The present study therefore provides up-to-date data based on which calculations could be made. The aim of this observational study is to describe the dynamic of the pandemic in Germany and identify the underlying characteristics of hospitalized patients from January 2020 until the end of December 2021, based on data from the German Institute for Hospital Remuneration System (InEK).

Materials and methods
Inclusion criteria. All hospitalized patients in Germany with proven SARS-CoV-2 infection between January 1st, 2020 and December 31th, 2021 were included.
Definitions and data acquisition. We divided patients into subgroups in dependence of admission to the ICU or to the general ward (non-ICU) and distinguished in both subgroups between survivors and nonsurvivors. The collected data included age, comorbidities (congestive heart failure, arterial hypertension, chronic pulmonary disease, diabetes and obesity), complications (acute renal failure, dialysis, cardiac arrhythmias, cardiopulmonary resuscitation (CPR), embolism, thrombosis, myocardial infarction, pulmonary embolism, intracranial hemorrhage and stroke), length of hospital stay and mortality. Due to our findings associated with obesity, we used and subdivided obesity according to the WHO-definition into grade I, II and III. Diagnoses were coded according to the tenth revision of the International Classification of Diseases (ICD) and procedures were coded according to the International Classification of Procedures in Medicine in the version of 2020 (Table 1). The InEK only allows anonymized queries; there is no possibility to track a case back to a patient and therefore no further analysis is possible at the individual case level. In this study, we included only patients with a confirmed SARS-CoV-2 infection by Real-Time-(RT)-PCR (ICD U07.1) and admitted to hospital between January 1st, 2020 and December 31th, 2021.
Existing comorbidities (e.g. arterial hypertension, ICD I10.x, I11.x-I13.x, I15.x) and complications were defined by their respective ICD codes (Table 1). Statistical analysis. The data were descriptively analyzed. Categorical variables are expressed as absolute numbers and percentages. Due to the lack of median and quartiles in the data source, continuous variables were Table 1. DRG and OPS codes. Allocation of diagnosis related groups (DRG) and operation and procedure (OPS) codes as they are coded for reimbursement purposes in Germany. Length of in-hospital stay (LOS) comorbidities, complications and mortality rate. In all patients the LOS was 11.2 (SD = 12.2) days in 2020 and 11.7 (SD = 12.4) days in 2021. The most common comorbidity in all hospitalized patients was arterial hypertension (51.94% n = 291,577), followed by congestive heart failure (24.32% n = 136,505). In the non-ICU-group arterial hypertension was the most common comorbidity in survivors (47.82% (n = 179,738)) and non-survivors (61.79% (n = 29,489)), followed by congestive heart failure www.nature.com/scientificreports/ (17.25% (n = 179,738) in survivors and 61.79% (n = 29,489) in non-survivors, respectively. All other comorbidities and their frequencies in subgroups are displayed in Table 3. The most common complication was cardiac arrhythmia overall, coded in 28.66% (n = 160,881) of the patients overall and in every subgroup, as well. Especially in non-survivor group in ICU patients 58.04% (n = 26,667) and non-ICU patients 45.99% (n = 21,946), respectively. In each non-survivor group the rates were significantly higher, compared to the survivor group (Table 3).
There is a significant difference between the groups of non-survivor/survivor within all complications (p < 0.001). The highest OR for the non-survivor groups were seen in CPR ( Table 4). Table 3. Comorbidities and complications. Comorbidities and complications among SARS-CoV-2 positive patients in Germany from Jan 2020 to end of December 2021. The percentages refer column wise to the corresponding group. OR odds ratio, CI confidence interval. www.nature.com/scientificreports/ Within the whole-time patients aged 60 years or older had the highest mortality in all hospitalized patients. Analyzed by the time trend of the data divided into months from January 2021 until the end of December 2021, in every month the highest mortality was observed in the age group 80-85 years, with particularly high mortality in months when hospitalization rates were the highest (Fig. 1, Table 4).

Discussion
This retrospective study includes a cohort of 561,379 hospitalized patients from January 1st, 2020 to December 31th, 2021 with a positive SARS-CoV-2 PCR test. Our main findings are a mortality rate of 16.69% overall. Between months of the ongoing pandemic, the mortality fluctuates. Especially in the "third wave", a noticeable decrease in the proportion of elderly patients was seen. The COVID-19 pandemic in Germany in the analyzed period can be described in four waves: the first one from March until May 2020 12 , the second one from October 2020 until January 2021 12 and a third wave from March until April 2021 13 . In the end of 2021 Germany went through the fourth wave. The cause of the undulating course of infection numbers is multifactorial, main reasons are higher temperatures in spring/summer 14 , social distancing and shutdown measures by the government 13 .
Mortality rate. The mortality rate of 16.69% overall is lower than previously described mortality-rates. Richardson et al. described 5700 hospitalized patients diagnosed with COVID-19 in New York from March until April 2020 and found a mortality rate of 21%, overall but a particularly lower rate of ICU-patients (12.2%) 15 . Karagiannidis et al. described over 10,000 patients suffering from COVID-19 in Germany from February until April 2020 in Germany and found a mortality rate of 22% overall 16 . This might be explained by the fact that previous studies describe a shorter time period. In December of 2020 the vaccine against COVID-19 was licensed in Germany 17 . Over time, more and more treatment options are being explored, and guidelines for the treatment of COVID-19 infection continue to evolve on a regular basis.
Due to prioritization rules the vaccines were only available for patients over 75 years of age, employees in high-risk facilities and patients with defined comorbidities were vaccicinated 17 . The prioritization was lifted in May 2021. The first "vaccination effect" may occur in January 2021, which could explain the decreasing proportion of patients aged 60 years or older from there on.
In contrast to that we found higher mortality rates in ICU patients, being 33.36%. A possible explanation might the higher capacity of ICU-beds in germany 16 and therefore the possibility to admit patients with more comorbidities or at higher age to the ICU, while in some countries ICUs reached their capacity limit 3 .
Our data shows a distinct mortality between minors (< 18 years) and old adults (> 60 years). Compared to the German population (17%, in 2020) and the share of SARS-CoV-2 infected persons (29%), the group of children (< 18 years) is significantly underrepresented among all hospitalised patients (2.35%, Table 2) 18,19 . Furthermore, 9% (< 18 years) against 26% (> 60 years) conditional on the respective group were admitted to ICU. There a various explanation for this finding. Children have less comorbidities such as obesity, diabetes, cancer and other chronic diseases. Children and adults show a different immune response to a viral infection, protecting children from severe COVID-19 20 . Our findings can also be explained with a difference in the expression of ACE2-receptor, the primary receptor of SARS-CoV-2 21 . Children express lower levels of ACE2 21 and therefore have fewer symptoms and a better prognosis 22 . Comorbidities. Arterial hypertension was the most common comorbidity in our study (51.94% (n = 291,577) overall), this result is in line with other studies describing hypertension as the most common comorbidity with rates of 42% 23 up to 56% 16 .
Obesity is known to be a risk factor for COVID-19 24 and is associated with higher mortality 11 . The incidence of 6.52% for obesity is lower than rates described in the UK (10.2%) 11 or France (47.6%) 25 . Surprisingly our data showed a reduced odd for death in patients with low grade obesity, especially WHO grade I (non-ICU: 0.55 (0.50-0.60) and ICU: 0.77 (0.72-0.82), respectively). Dana et al. found a lower risk of death for critically ill COVID-19 patients among patients with moderate obesity 26 . This finding is not in line with other studies 27 . However, the Centers for Disease Control and Prevention (CDC) states that patients at the "threshold" between healthy weight and overweight are at lower risk for hospitalization, ICU admission, and death while the risk for mechanically ventilation raised continuously with rising body mass index (BMI) 28 . Our findings support the statement of the CDC. Patients with a low grade overweight (WHO grade I) have a higher chance of survival (With increasing obesity, the effect is lost and the overweight becomes a risk factor for the patient (WHO grade III, OR: 1.13 (1.08-1.19)). However, overweight and moderate obesity are known to have a protective effect on hospitalized non-COVID-19 ICU-Patients 29 . This effect is not yet fully understood and often controversially referred to as "obesity paradox" 30 . With a lower rate of high grade obese patients admitted to the hospital, more patients are at the "threshold" described by the CDC. Foo et al. described for every 1% increase in obesity prevalence, the COVID-19 mortality rate was increased by 8.3% 31 . This might explain our finding.
We could find a significant difference in the frequency of patients suffering from congestive heart failure between survivors and non-survivors, with a bigger frequency of heart failure in non-survivors. One possible explanation is that patients suffering from heart failure have a higher overall frailty and are at higher risk for acute cardiac injury. Several studies investigated cardiovascular manifestations and mechanisms in patients suffering from COVID-19 and showed a high prevalence of cardiovascular comorbidities 32 and a higher risk for mortality in patients suffering from cardiovascular comorbidities or cardiac injury 32,33 . Jabri et al. described a significant increase in stress cardiomyopathy during the pandemic 34 , furthermore a frequent occurrence of cor pulmonale in COVID-19 patients has been described 35 . All this factors explain the high proportion of cardiac comorbidities in hospitalized patients and the increase of those diagnoses in the non-survivor groups.

Complications.
We found arrhythmias to be the most common complication in our study. We showed a rate of 42.74% (n = 58,870) for ICU patients. This result is comparable to a study by Duo et al. who described a rate of 44.4% among ICU patients in a study investigating 138 patients overall 32 .
Electrocardiographic abnormalities are often described in patients suffering from COVID-19 36 www.nature.com/scientificreports/ One underlying reason may be the mismatch between oxygen supply and oxygen demand resulting in cardiac injury. Therefore, the high OR for death is not surprising.
Thrombotic events are often seen in COVID-19 patients. Those events are associated with a more severe disease and increased mortality 38,39 . The molecular explanation range from COVID-19-associated coagulopathy to genetic predisposition and is still subject to research 40,41 . Our findings are in line with literature, we showed a pulmonary embolism rate of 2.27% (n = 12,730) for all hospitalized COVID-19 patient. Patients suffering from pulmonary embolism have a higher chance of dying (OR: 2.14 (2.05-2.22)). OR on ICU is lower (OR: 1.35 (1.28-1.41). One explanation for this could be that more radiological examinations are performed on ICU and therefore associated with a higher number of incidental findings without clinical relevance 42 . A second explanation is that patients on ICU are more likely to be sufficiently anticoagulated, as recommended in guidelines 43,44 . Unfortunately, medication application such as anticoagulation is not provided in the reimbursement data.
Renal failure is a common complication in patients suffering from COVID-19 15,45 . The observed rate of patients with acute kidney failure (17.98% n = 100,926) is in line with other studies, describing rates between 20 and 40% 15,45 . The higher proportion of patients with renal replacement therapy (RRT) in the ICU-group might be explained by the fact that needing dialysis is a common reason to be admitted to the ICU. Patients who had been diagnosed with acute kidney failure and a following admission to the ICU are displayed in the ICU-group only. In our study 5.67% (n = 31,847) patients needed RRT, this result seems to be higher than in other studies, for example Richardson et al. described a rate of 3.2%.
COVID-19 patients are more likely to suffer from in-hospital-cadiac-arrest (IHCA) 46 . In our study 1.73% (n = 9728) of all patients received CPR. The OR of dying was remarkably higher on the normal ward compared to the ICU. This is in accordance to the literature. Acharya et al. described a IHCA for non-ICU patients in 2.2% (in our study: 2.48%) and for ICU patients in 15.4% (in our study 14.2%) 47 . A possible cause for the high difference between non-ICU and ICU patients might be the longer timespan between the circulatory arrest and the actual start of CPR due to the lack of monitoring 48 .
This study is the first in Germany to describe the course of the pandemic from the beginning to the end of December 2021, covering 561 379 hospitalized COVID-19 Patients.
Further studies should be conducted to identify risk factors for an adverse course of the disease. On one hand, this could help to identify patients with a special risk profile at an early stage (for example Simonnet et al. investigated obesity as a risk factor 25 ) or, on the other hand, serve as criteria in possible triaging.

Conclusion
The overall mortality rate of 16.69% in COVID-19 patients in Germany is lower than previously shown in other studies. 24.54% of all patients had to be treated on the ICU with a mortality rate of 33.36%, which was high in comparison to the literature. Congestive heart failure was associated with a significantly higher risk of death. In non-ICU patients suffering from congestive heart failure the OR was especially high, being 4.23 (4.15-4.31). The most common comorbidity in all COVID-19 patients was arterial hypertension. The most common complication were arrhythmias, which were diagnosed significantly more often in non-survivors (p < 0.001). In COVID-19 patients CPR is associated with a high chance of death, especially on normal wards (OR: 85.36 (70.31-103.64)). With an OR: 0.83 (0.79-0.87) WHO grade I obesity might have a protective effect of the patient's survival.
Pre-existing cardiac conditions appear to carry a particularly high risk in patients suffering from COVID-19. Due to the limited data, no further research could be done, so it is extremely important to make this data available to the scientific community in order to gain a wider insight and better understand possible causal relationships.
Limitations. Due to the provision of data by the InEK during the year, only highly aggregated data are available and no further detailed queries are possible. Patients' age is only available in the provided subgroups, so no further analysis like mean or median age can be made. As the data (e.g. comorbidities) were anonymized and cannot be tracked back to a single patient further analysis such as linear regression are not possible. Laboratory findings or medication are not coded for reimbursement and are therefore not available for analysis.

Data availability
The German Institute for Hospital Remuneration System (InEK) supports hospitals and health insurance funds as well as their associations in the introduction and continuous further development of the German-DRG system in accordance with the Krankenhausfinanzierungsgesetz (KHG; Hospital Financing Act). Since 2020, access to these data has been possible during the year. For this observational study, we used publicly accessible performance data provided by InEK. Since the register data were anonymized, the Ethics Committee of the University Hospital www.nature.com/scientificreports/